Arylpiperazines having activity at the serotonin 1A receptor

ABSTRACT

A series of aryl piperazine compounds are effective pharmaceuticals for the treatment of conditions related to or affected by the serotonin 1 A  receptor; the compounds are particularly effective antagonists at that receptor, and are particularly useful for alleviating the symptoms of nicotine and tobacco withdrawal.

CROSS REFERENCE

[0001] This application claims the benefit of U.S. ProvisionalApplication Nos. 60/069,722 filed Dec. 16, 1997, 60/069,791 filed Dec.16, 1997 and 60/089,589 filed Jun. 17, 1998.

FIELD OF THE INVENTION

[0002] The present invention belongs to the fields of pharmacology andmedicinal chemistry, and provides new pharmaceuticals which are usefulfor the treatment of diseases which are caused or affected by disordersof the serotonin-affected neurological systems, particularly thoserelating to the 1_(A) receptor.

BACKGROUND OF THE INVENTION

[0003] Pharmaceutical researchers have discovered in recent years thatthe neurons of the brain which contain monoamines are of extremeimportance in a great many physiological processes which very stronglyaffect many psychological and personality-affecting processes as well.In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found tobe a key to a very large number of processes which affect bothphysiological and psychological functions. Drugs which influence thefunction of serotonin in the brain are accordingly of great importanceand are now used for a surprisingly large number of different therapies.

[0004] The early generations of serotonin-affecting drugs tended to havea variety of different physiological functions, considered from both themechanistic and therapeutic points of view. More recently, it has becomepossible to study the function of drugs at individual receptors in vitroor ex vivo, and it has also been realized that therapeutic agents with asingle mechanism of action are often advantageous to the patient.Accordingly, the objective of research now is to discover not onlyagents which affect only functions of serotonin, but agents which affectonly a single function of serotonin, at a single identifiable receptor.

[0005] The present invention provides compounds which have highlyselective activity as antagonists of the serotonin 1_(A) receptor.

SUMMARY OF THE INVENTION

[0006] The present invention provides a series of new aryl piperazinecompounds, methods of using them for pharmaceutical purposes, andpharmaceutical compositions whereby the compounds may be convenientlyadministered.

[0007] The invention also provides methods of antagonizing, the5HT-1_(A) receptor, and therapeutic methods which are related to theireffect on the 5HT-1_(A) receptor. Such methods of treatment include,particularly, methods of alleviating the symptoms caused by withdrawalor partial withdrawal from the use of tobacco or of nicotine, comprisingthe administration to a patient in need of such treatment of a compoundof Formula I

[0008] wherein

[0009] Ar′ is a mono- or bi-cyclic aryl or heteroaryl radicalsubstituted with one to three substituents selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkenyl or halo;

[0010] R¹ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio;

[0011] R² is phenyl, naphthyl or (C₃-C₁₂)cycloalkyl substituted with oneor two substituents selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo;

[0012] R³ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo;

[0013] X is —C(═O)—, —CHOH— or —CH₂—;

[0014] or a pharmaceutically acceptable salt, racemate, optical isomeror solvate thereof.

[0015] Further, such therapeutic methods include methods of treatment ofanxiety, depression, hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, eating disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine.

[0016] A further treatment method provided by the present invention is amethod for potentiating the action of a serotonin reuptake inhibitor,comprising administering to a patient an effective amount of a compoundof Formula I in combination with the serotonin reuptake inhibitor.

[0017] More specifically, the present invention provides compounds offormula Ia;

[0018] or the pharmaceutically acceptable salts thereof.

[0019] The compounds of formula Ia are enclosed within the scope of thecompounds of Formula I and are therefore useful for the methodsdescribed herein for Formula I. For example, the present inventionprovides methods of antagonizing, the 5HT-1_(A) receptor, andtherapeutic methods which are related to their effect on the 5HT-1_(A)receptor. Such methods of treatment include, particularly, methods ofalleviating the symptoms caused by withdrawal or partial withdrawal fromthe use of tobacco or of nicotine, comprising the administration to apatient in need of such treatment, an effective amount of a compound offormula Ia. Further, such therapeutic methods include methods oftreatment of anxiety, depression, hypertension, cognitive disorders,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, eating disorders and obesity,substance abuse, obsessive-compulsive disease, panic disorder andmigraine.

[0020] In addition, the present invention provides a method forpotentiating the action of a serotonin reuptake inhibitor, comprisingadministering to a patient an effective amount of a compound of formulaIa in combination with the serotonin reuptake inhibitor.

[0021] The invention further provides a method of assisting a patient inceasing or reducing their use of tobacco or nicotine comprisingadministering to a patient an effective amount of a compound of theFormula I or formula Ia.

[0022] This invention also encompasses novel processes for the synthesisof the compounds of formula I and formula Ia, the synthesis of novelintermediates thereof, and further encompasses novel intermediates perse.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0023] In the present document, all descriptions of concentrations,amounts, ratios and the like will be expressed in weight units unlessotherwise stated. All temperatures are in degrees Celsius.

[0024] The Compounds

[0025] It is believed that the general description of the compoundsabove is sufficient to explain their nature to the skilled reader;attention to the Examples which follow is also encouraged. Someadditional description will be provided to assure that nomisunderstanding occurs.

[0026] In the general description, the general chemical terms are allused in their normal and customary meanings. For example, the smallalkyl and alkoxy groups, such as (C₁-C₆)alkyl and (C₁-C₆)alkoxy groupsinclude, depending on the size of the groups, methyl, ethyl, propyl,isopropyl, n-butyl, s-butyl, pentyl, 3-methylbutyl, hexyl, and branchedhexyl groups, and the corresponding alkoxy groups, as may be allowed bythe individually named groups. Where a number of possible substituentgroups are permitted on a group, such as the one to three alkyl, alkoxyor halo groups permitted on an Ar group, it will be understood by thereader that only substitution which is electronically and stericallyfeasible is intended.

[0027] The term “alkenyl” as used herein represents an unsaturatedbranched or linear group having at least one double bond. Examples ofsuch groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl as well as dienes and trienes of straight and branched chains.

[0028] The term “alkynyl” denotes such radicals as ethynyl, propynyl,butynyl, pentynyl, hexynyl as well as di- and tri-ynes.

[0029] The term “(C₁-C₆)alkylthio” defines a straight or branched alkylchain having one to six carbon atoms attached to the remainder of themolecule by a sulfur atom. Typical (C₁-C₆)alkylthio groups includemethylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio andthe like.

[0030] The term “(C₁-C₆)alkylhalo” refers to alkyl substituents havingone or more independently selected halo atoms attached at one or moreavailable carbon atoms. These terms include chloromethyl, bromoethyl,trifluoroethyl, trifluoromethyl, 3-bromopropyl, 2-bromopropyl,3-chlorobutyl, 2,3-dichlorobutyl, 3-chloro-2-bromo-butyl,trichloromethyl, dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl,1,3-dichlorobutyl, 1,1-dichloropropyl, and the like. More preferred(C₁-C₆)alkylhalo groups are trichloromethyl, trichloroethyl, andtrifluoromethyl. The most preferred (C₁-C₆)alkylhalo is trifluoromethyl.

[0031] The term “(C₃-C₈)cycloalkyl” includes groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Theterm “(C₃-C₈)cycloalkyl” includes (C₃-C₆)cycloalkyl.

[0032] The term “(C₃-C₈)cycloalkenyl” represents an olefinicallyunsaturated ring having 3 to 8 carbon atoms including groups such ascyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, and the like. The term “(C₃-C₈)cycloalkenyl” includes(C₃-C₆)cycloalkenyl.

[0033] The term “aryl” represents phenyl or naphthyl.

[0034] The term “bicyclic” represents either an unsaturated or saturatedstable 7- to 12-membered bridged or fused bicyclic carbon ring. Thebicyclic ring may be attached at any carbon atom which affords a stablestructure. The term includes, but is not limited to, naphthyl,dicyclohexyl, dicyclohexenyl, and the like.

[0035] The term, “mono or bicyclic heteroaryl radical”, refers toradicals derived from monocyclic or polycyclic, aromatic nuclei having 5to 14 ring atoms and containing from 1 to 3 hetero atoms selected fromthe group consisting of nitrogen, oxygen or sulfur. Typical heterocyclicradicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,indolizinyl, isoquinolyl, benzothienyl, isoindolizinyl, oxazolyl,indolyl, carbazolyl, norharmanyl, azaindolyl, dibenzofuranyl,thianaphthenyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl,anthranilyl, purinyl, pyridinyl, phenylpyridinyl, pyrimidinyl,pyrazinyl, quinolinyl.

[0036] The terms “halo” or “halide” are used in the above formula torefer to fluoro, chloro, bromo or iodo.

[0037] The term “aprotic solvent” refers to polar solvents of moderatelyhigh dielectric constant which do not contain an acidic hydrogen.Examples of common aprotic solvents are dimethylsulfoxide (DMSO),dimethylformamide, sulfolane, tetrahydrofuran, diethyl ether,methyl-t-butyl ether, or 1,2-dimethoxyethane.

[0038] The term “protic solvent” refers to a solvent containing hydrogenthat is attached to oxygen, and hence is appreciably acidic. Commonprotic solvents include such solvents as water, methanol, ethanol,2-propanol, and 1-butanol.

[0039] The term “inert atmosphere” refers to reaction conditions inwhich the mixture is covered with a layer of inert gas such as nitrogenor argon.

[0040] As used herein, the term “Me” refers to a —CH₃ group, the term“Et” refers to a —CH₂CH₃ group and the term “Pr” refers to a —CH₂CH₂CH₃group.

[0041] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. As used herein, the term“optical isomer” is equivalent to the term “enantiomer”. The terms“racemate”, “racemic mixture” or “racemic modification” refer to amixture of equal parts of enantiomers. The term “chiral center” refersto a carbon atom to which four different groups are attached.

[0042] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0043] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 50:30 isachieved, the ee with respect to the first enantiomer is 25%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, theenantiomers of compounds of formulas I or Ia can be resolved by one ofordinary skill in the art using standard techniques well known in theart, such as those described by J. Jacques, et al., “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981. Examplesof resolutions include recrystallization techniques or chiralchromatography.

[0044] The compounds of Formula I and formula Ia, as a class are highlyactive, important and particularly useful in the treatment methods ofthe present invention, but certain classes of the compounds arepreferred. The following paragraphs describe such preferred classes. Itwill be understood that the preferred classes are applicable both to thetreatment methods and to the new compounds of the present invention.

[0045] The reader will understand that the preferred classes ofcompounds may be combined to form additional, broader or narrowerclasses of preferred compounds.

[0046] a) Ar′ is phenyl or pyridyl;

[0047] b) Ar′ is naphthyl;

[0048] c) Ar′ is pyrazinyl, pyrimidinyl, pyrrolyl, furyl, thienyl,indolyl, purinyl, imidazolyl, pyrazolyl, indolizinyl, benzofuranyl,isoquinolyl, quinolyl, benzothienyl or isoindolizinyl;

[0049] d) Ar′ is optionally substituted with (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl;

[0050] e) Ar′ is optionally substituted with (C₁-C₄)alkyl, (C₁-C₄)alkoxyor halo;

[0051] f) R¹ is hydrogen;

[0052] g) R¹ is (C₁-C₆)alkyl or (C₁-C₆)alkoxy;

[0053] h) R¹ is (C₁-C₂)alkyl or (C₁-C₂)alkoxy;

[0054] i) R² is phenyl;

[0055] j) R² is (C₃-C₈)cycloalkyl;

[0056] k) R² is (C₃-C₆)cycloalkyl;

[0057] l) R² is cyclohexyl;

[0058] m) R³ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halo;

[0059] n) R³ is (C₁-C₄)alkyl, (C₁-C₄)alkoxy or halo;

[0060] o) X is —C═O;

[0061] p) X is —CHOH; and

[0062] q) X is —CH₂.

[0063] r) formula Ia

[0064] s) the enantiomer of formula Ia wherein the [α]^(D) ₂₀ inmethanol is (+).

[0065] Since the compounds of this invention are basic in nature, theyaccordingly react with any of a number of inorganic and organic acids toform pharmaceutically acceptable acid addition salts. Included withinthe scope of the invention are the mono- and di-salts. Acids commonlyemployed to form such salts are inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,and the like, and organic acids, such as p-toluenesulfonic acid,methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonicacid, succinic acid, citric acid, benzoic acid, acetic acid and thelike. Examples of such pharmaceutically acceptable salts thus are thesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,β-hydroxybutyrate, glycollate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate and the like. Preferred pharmaceutically acceptable salts arethe monohydrochloride, dihydrochloride, monohydrobromide,dihydrobromide, Formula I/succinate(1:1), formula Ia/succinate(1:1),Formula I/succinate 2:1, formula Ia/succinate 2:1, phosphate,d-tartrate, 1-tartrate or maleate. It is understood by one of ordinaryskill that hydrates of the free base or of the pharmaceuticallyacceptable salts are included within the scope of the present invention.

[0066] Many of the compounds of Formula I, including formula Ia, areoptical isomers. For example, the compounds have an asymmetric center(or chiral center) at the carbon atom to which R¹ and X are attached.However, when a compound of the present invention is named without anindication of asymmetric form, any and all of the possible asymmetricforms are intended. This invention is not limited to any particularisomer but includes all possible individual isomers and racemates.

[0067] The intermediates and final products may be isolated and purifiedby conventional techniques, such as, purification with chromatographyusing silica gel or recrystallization of crystalline isolates.

[0068] It will be readily appreciated by the skilled artisan that thestarting materials which are not described are either commerciallyavailable or can be readily prepared by known techniques fromcommercially available starting materials. All other reactants used toprepare the compounds in the instant invention are commerciallyavailable.

[0069] The compounds of the invention are generally prepared accordingto the following schemes.

[0070] Starting material (1) is treated with a base, preferablypotassium tert-butoxide, followed by alkylation with2-bromomethyl-1,3-dioxolane. other appropriate bases include sodiumhydride, sodium hydroxide, potassium hydroxide, potassium carbonate,cesium carbonate and the like.

[0071] The reaction is preferably conducted in a solvent such asdimethyl sulfoxide at a temperature of 15° C. to reflux, with atemperature of 45-55° C. being most preferred, and is substantiallycomplete in 1 to 24 hours to prepare intermediate (2).

[0072] Treatment of (2) with an acid, such as hydrochloric acid orp-toluene-sulfonic acid in a suitable organic solvent, achieves aldehyde(3). Generally, the reaction is conducted in a protic solvent, such amixture of aqueous acid and acetone, at temperatures of from about 5° to75° C., preferably at ambient temperature.

[0073] Aldehyde (3) is coupled with the desired aryl piperidine (4) byreductive amination to prepare (5). The reaction is preferably conductedat ambient temperature in a non-reactive solvent such as dichloroethaneor methylene chloride in the presence of sodium triacetoxyborohydrideand is substantially complete in one to 24 hours. See for example A. F.Abdel-Magid, et al., J. Org. Chem., 61, 3849 (1996).

[0074] Reduction of (5) is readily accomplished using a reducing agentsuch as sodium borohydride or, preferably, diisobutylaluminum hydride toprepare the hydroxy compound (6). The reaction is preferably conductedin an organic solvent such as methylene chloride at temperatures of fromabout −20° C. to 0° C.

[0075] Further reduction of (6) to achieve product (7) may be achievedby treatment with a reducing agent such as triethylsilane or borontrifluoride (when R² is phenyl or substituted phenyl) or by treatmentwith an acid, such as hydrochloric acid or trifluoroacetic acid, in anaprotic solvent such as tetrahydrofuran, at ambient temperature to formthe double bond, followed by hydrogenation with, for example, hydrogenand palladium on carbon.

[0076] Starting material (1) is either commercially available or can beprepared by coupling (8) [See Nahm and Weinreb, Tetrahedron Lett., 22,3815, (1981)] and (9) as described in Scheme II, below.

[0077] M is a metallic salt, such as lithium or magnesium halide. Thereaction is preferably conducted under an inert atmosphere preferablynitrogen, in an aprotic solvent, such as tetrahydrofuran, at ambienttemperatures.

[0078] More specifically, the compounds of formula Ia can be preparedfollowing the procedure described in Scheme III. All substituents,unless otherwise indicated, are previously defined. The reagents andstarting materials are readily available to one of ordinary skill in theart.

[0079] In Scheme III, step A, the ester of structure (10) is treatedwith benzylmagnesium chloride or benzylmagnesium bromide under standardconditions well known in the art to provide the ketone of structure(11). For example, about 1.05 to about 1.1 equivalents of a suitableamine, such as dimethylamine is dissolved in a suitable organic solvent,such as tetrahydrofuran (cooled to about −5° C.) under an inertatmosphere. The solution is warmed to room temperature and 1.0equivalents of the ester (10) are added with stirring. Thenapproximately 1.0 to 1.05 equivalents of benzylmagnesium chloride isslowly added to the solution, maintaining the temperature at about15-20° C. with a cooling bath during the addition. After addition iscomplete, the reaction is stirred at room temperature for about 1 to 2hours, then cooled to less than 0° C. and then carefully quenched with asuitable acid, such as HCl. The quenched reaction is then extracted witha suitable organic solvent, such as tert-butyl methyl ether (hereinafterreferred to as MTBE), the organic layers are combined, dried overanhydrous magnesium sulfate, filtered and concentrated to provide ketone(11). Ketone (11) can be purified by techniques well known in the art,such as flash chromatography on silica gel with a suitable eluent, suchas ethyl acetate/hexane to provide the purified material. Alternatively,the crude ketone (11) can be carried on to step B.

[0080] In Scheme III, step B, ketone (11) is alkylated withbromoacetaldehyde diethyl acetal, and then iodomethane, under conditionswell known in the art to provide compound of structure (12). Forexample, ketone (11) is dissolved in a suitable organic solvent, such asmethyl sulfoxide and treated with about 1.05 to about 1.1 equivalents ofa suitable base, such as potassium tert-butoxide. The reaction isstirred for about 15 to 30 minutes and about 1.0 to about 1.05equivalents of bromoacetaldehyde diethyl acetal is added dropwise to thereaction. One of ordinary skill in the art would readily appreciate thatbromoacetaldehyde dimethyl acetal, bromoacetaldehyde ethylene acetal andthe like may be used in place of the corresponding diethyl acetal. Thereaction mixture is then heated to about 50° C. for about 2 to 2.5hours. The reaction mixture is then cooled with an ice/water bath andabout 2.2 equivalents of a suitable base, such as potassiumtert-butoxide is added. The reaction is allowed to stir for about 15 to30 minutes with continued cooling and then about 1.5 to about 1.8equivalents of iodomethane is added dropwise to the reaction mixturekeeping the temperature of the mixture below 41° C., preferably below21° C. After addition is complete, the reaction is warmed to roomtemperature and stirred for about 1 to 4 hours. The reaction mixture isthen partitioned between water and a suitable organic solvent, such asMTBE. The layers are separated and the organic phase is washed withwater, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the compound (12).

[0081] In Scheme III, step C, compound (12) is hydrolyzed under acidicconditions to provide aldehyde (13) in a manner analogous to theprocedure described in Scheme I. More specifically, for example,compound (12) is dissolved in a suitable organic solvent, such asacetone and treated with a suitable acid, such as hydrochloric acid. Thereaction mixture is stirred for about 1 to 3 hours at room temperature.The reaction mixture is then extracted with a suitable organic solvent,such as ethyl acetate or methylene chloride, the organic extracts arecombined, washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum to provide aldehyde (13).Aldehyde (13) can be purified by techniques well known in the art, suchas flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane. Alternatively, crude aldehyde (13) can be useddirectly in step D.

[0082] In Scheme III, step D, aldehyde (13) is reductively aminated,under conditions well known in the art, with piperazine (14) to providethe compound of formula Ia in a manner analogous to the proceduredescribed in Scheme I. More specifically, for example, aldehyde (13) isdissolved in a suitable organic solvent, such as methylene chloride. Tothis solution is added about 1.1 equivalents of piperazine (14). Aceticacid may optionally be added to aid in dissolution of the piperazine(14). Then about 1.2 to 1.3 equivalents of sodium triacetoxyborohydrideis added and the reaction is stirred at room temperature for about 3 to5 hours. The reaction is then quenched by addition of a suitable base,such as aqueous sodium hydroxide to provide a pH of about 10 to about12. The quenched reaction is then extracted with a suitable organicsolvent, such as methylene chloride. The organic extracts are combined,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the compound of formula Ia. Thismaterial can then be purified by techniques well known in the art, suchas flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane.

[0083] The free base of formula Ia can be converted to the correspondingpharmaceutically acceptable salts under standard conditions well knownin the art. For example, the free base of formula Ia is dissolved in asuitable organic solvent, such as methanol, treated with one equivalentof maleic or oxalic acid for example, or two equivalents of hydrochloricacid for example, and then concentrated under vacuum to provide thecorresponding pharmaceutically acceptable salt. The residue can then bepurified by recrystallization from a suitable organic solvent or organicsolvent mixture, such as methanol/diethyl ether.

[0084] In Scheme III, step E, the (+) enantiomer of formula Ia can beseparated from the (−) enantiomer using techniques and procedures wellknown in the art, such as that described by J. Jacques, et al.,“Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc.,1981. For example, chiral chromatography with a suitable organicsolvent, such as ethanol/acetonitrile and Chiralpak AD packing, 20micron can also be utilized to effect separation of the enantiomers.

[0085] In Scheme III, step F, the (+) enantiomer of formula Ia isconverted to its pharmaceutically acceptable salt, such as themonohydrochloride, dihydrochloride, monohydrobromide, dihydrobromide,formula Ia/succinate(1:1), formula Ia/succinate 2:1, phosphate,d-tartrate, 1-tartrate or maleate salt, in a manner analogous to theprocedure described at the end of step D above.

[0086] Alternatively, compounds of structure (5) can be preparedfollowing the procedure described in Scheme IV. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

[0087] In Scheme IV, step A, aldehyde (15) is combined with a suitableorganometallic reagent (16) under conditions well known in the art toprovide alcohol (17). Examples of suitable organometallic reagentsinclude Grignard Reagents, alkyl lithium reagents, alkyl zinc reagents,and the like. Grignard Reagents are preferred. For examples of typicalGrignard Reagents and reaction conditions, see J. March, “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure”, 2^(nd)Edition, McGraw-Hill, pages 836-841 (1977). More specifically, aldehyde(15) is dissolved in a suitable organic solvent, such as tetrahydrofuranor toluene, cooled to about −5° C. and treated with about 1.1 to 1.2equivalents of a Grignard reagent of formula (16) wherein M is MgCl orMgBr. The reaction is allowed to stir for about 0.5 to 2 hours, thenquenched, and alcohol (17) is isolated. For example, the reactionmixture is poured onto ice-cold 1N HCl, the quenched mixture isextracted with a suitable organic solvent, such as toluene, the organicextracts are dried either azeotropically or over a suitable dryingagent, such as anhydrous magnesium sulfate, filtered and concentratedunder vacuum to provide alcohol (17).

[0088] In Scheme IV, step B, alcohol (17) is oxidized under standardconditions well know in the art, such as those described by J. March,“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”,2^(nd) Edition, McGraw-Hill, pages 1082-1084 (1977), to provide ketone(1). [Ketone (1) is the starting material used in Scheme I above.]

[0089] For example, alcohol (17) is dissolved in a suitable organicsolvent, such as methylene chloride, the solution cooled with a wetice-acetone bath, and treated with 2.5 to 3.0 equivalents of dimethylsulfoxide. After stirring for about 30 minutes, the reaction is thentreated with about 1.8 equivalents of P₂O₅. The reaction is allowed tostir for about 3 hours and then, preferably, treated over about 30minutes with about 3.5 equivalents of a suitable amine, such astriethylamine. The cooling bath is then removed and the reaction isallowed to stir for about 8 to 16 hours. The ketone (1) is then isolatedby standard extraction techniques well known in the art. The aboveoxidation is also performed using standard Swern Oxidation conditionswhich are well known to one of ordinary skill in the art.

[0090] In Scheme IV, step C, ketone (1) is treated with a suitable basefollowed by addition of the alkene (18), wherein X is a suitable leavinggroup, to provide compound (19). For example, ketone (1) is combinedwith an excess of alkene (18) in a suitable organic solvent, such astetrahydrofuran, and cooled with a wet ice acetone bath. Examples ofsuitable leaving groups are Cl, Br, I, tosylate, mesylate, and the like.Preferred leaving groups are Cl and Br. About 1.1 equivalents of asuitable base is added and the reaction is allowed to stir for about 2hours at room temperature. Examples of suitable bases are potassiumtert-butoxide, sodium hydride, NaN(Si(CH₃)₃)₂, LDA, KN(Si(CH₃)₃)₂,NaNH₂, sodium ethoxide, sodium methoxide and the like. Potassiumtert-butoxide is the preferred suitable base. The reaction is thenquenched with aqueous acid and compound (19) is isolated by extractionwith a suitable organic solvent, such as heptane. The heptane extractsare washed with sodium bicarbonate, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum to provide compound(19).

[0091] In Scheme IV, step D, compound (19) is treated with a suitableoxidizing agent to provide aldehyde (3). [Aldehyde (3) is also preparedin Scheme I.] Examples of suitable oxidizing agents are ozone,NaIO₄/Osmium catalyst, and the like. Ozone is the preferred oxidizingagent. Examples of suitable oxidizing reagents and conditions aredescribed by J. March, “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure”, 2^(nd) Edition, McGraw-Hill, pages 1090-1096(1977).

[0092] For example, compound (19) is dissolved in a suitable organicsolvent, such as methanol, a small amount of Sudan III is added, and thesolution is cooled to about −20° C. Ozone is bubbled into the solutionfor about 4 hours until the pink color turns to a pale yellow color.Then Me₂S is added to the reaction mixture and the cooling bath isremoved. Concentration of the reaction mixture under vacuum provides theintermediate dimethyl acetal of aldehyde (3). This dimethyl acetal isreadily hydrolyzed under standard acidic conditions to provide aldehyde(3). Alternatively, direct acidic work-up of the crude reaction mixtureprovides aldehyde (3). Alternatively, aldehyde (3) can be obtaineddirectly by ozonolysis of (19) in a non-acetal forming solvent, such asmethylene chloride.

[0093] In Scheme IV, step E, aldehyde (3) is reductively aminated underconditions analogous to those described above in Scheme III, step D, toprovide compound (5). [Compound 5 is also prepared in Scheme I.]

[0094] Scheme V provides an alternative synthesis for the preparation ofcompound (5). All substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art.

[0095] In Scheme V, step A, aldehyde (3) is condensed with piperidine(4) under standard conditions well known in the art to provide theenamine (20). For example, about 1.05 equivalents of aldehyde (3)dissolved in a suitable organic solvent, such as isopropyl acetate orisopropanol, is added to neat piperazine (4), free base. Additionalorganic solvent is added to produce a slurry and the reaction is stirredfor about 1 to 2 hours. The enamine (20) is then isolated by standardtechniques, such as collection by filtration.

[0096] In Scheme V, step B, the enamine (20) is hydrogenated underconditions well known by one of ordinary skill in the art to providecompound (5). For example, enamine (20) is combined with a suitableorganic solvent, such as isopropyl alcohol and a catalytic amount of 5%palladium on carbon in a Parr bottle. The mixture is placed under 50 psiof hydrogen and shaken for about 2 days at room temperature. The slurryis then filtered to remove catalyst and the filtrate is concentrated toprovide compound (5).

[0097] The following examples represent typical syntheses of thecompounds of Formula I and formula Ia as described generally above.These examples are illustrative only and are not intended to limit theinvention in any way. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. As used herein, thefollowing terms have the meanings indicated: “aq” refers to aqueous;“eq” refers to equivalents; logic refers to grams; “mg” refers tomilligrams; “L” refers to liters; “mL” refers to milliliters; “μL”refers to microliters; “mol” refers to moles; “mmol” refers tomillimoles; “psi” refers to pounds per square inch; “min” refers tominutes; “h” refers to hours; “° C.” refers to degrees Celsius; “TLC”refers to thin layer chromatography; “HPLC” refers to high performanceliquid chromatography; “R_(f)” refers to retention factor; “R_(t)”refers to retention time; “δ”refers to part per million down-field fromtetramethylsilane; “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “IPA” refers to isopropyl alcohol; “iPrOAc”refers to isopropyl acetate; “AcOH” refers to acetic acid; “HRMS” refersto high resolution mass spectrometry; “Et₃N” refers to triethylamine;“LDA” refers to lithium diisopropyl amide; “RT” refers to roomtemperature; “SRI” refers to serotonin reuptake inhibitor; “aq” refersto aqueous; and “MTBE” refers to tert-butyl methyl ether.

EXAMPLE 1

[0098]

1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine oxalate

[0099] A. Preparation of 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane:

[0100] To a stirred suspension of sodium hydride (61.25 mmol) in 150 mLof dimethylformamide at 0° C. under nitrogen was added dropwise asolution of deoxybenzoin (50.96 mmol) in 150 mL of tetrahydrofuran. Themixture was stirred at 0° C. for 1 hour and room temperature for 1 hour.To the mixture 2-bromomethyl-1,3-dioxolane (60.55 mmol) and catalystpotassium iodide (6.0 mmol) were added. The mixture was heated to refluxfor 13 hours. After cooling, diethyl ether (300 mL) and water (300 mL)were added. The organic layer was separated and washed with water (150mL×2). Purification by flash chromatography using hexanes and ethylacetate gave 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (8.18 g; 57%).

[0101] B. Preparation of 3-benzoyl-3-phenylpropionaldehyde.

[0102] To 100 mL of acetone was added2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (8.85 mmol) and 100 mL of 2Nhydrochloric acid solution. After the mixture was stirred at roomtemperature for 7 hours, 100 mL of 2N sodium hydroxide was added.Acetone was evaporated and the residue was extracted with diethyl etherand hexanes (1:1, 100 mL×3). The combined organic layer was dried(sodium sulfate), filtered and concentrated. The residue was found to berather pure material (3-benzoyl-3-phenylpropionaldehyde) and thereforeused for next step.

[0103] C. Preparation of1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine.

[0104] The 3-benzoyl-3-phenylpropionaldehyde residue obtained from StepB, above, (˜8.85 mmol) was dissolved in 110 mL of methylene chloride. Tothis solution was added 2-methoxyphenylpiperazine (10.61 mmol) andsodium triacetoxyboranehydride, NaBH(OAc)₃, (10.61 mmol). The mixturewas stirred at room temperature for 3 hours. Aqueous workup followed byflash chromatography gave pure product1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine (3.48 g)in 95% yield for last two steps. One equivalent of oxalic acid was addedto the free base dissolved in methanol. The solvent was evaporated andthe product was dried under vacuum to form the oxalate salt.

[0105] m.p.=161-163° C.;

[0106] MS (m/e): 414 (M⁺).

EXAMPLE 2

[0107]

1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazineoxalate

[0108] A. Preparation of cyclohexyl benzyl ketone.

[0109] To a stirred solution of N-methyl-N-methoxycyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C.under nitrogen was added a solution of benzyl magnesium chloride (2.0 Min tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C.for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL)and water (20 mL) were added. The organic layer was separated, dried,filtered, and concentrated. Purification of the residue by flashchromatography using hexanes and ethyl acetate gave cyclohexyl benzylketone (1.05 g) in 70% yield as oil.

[0110] B. Preparation of2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane.

[0111] Following the procedures described in the Example 1, Step A, thereaction of cyclohexyl benzyl ketone (5.09 mmol) and2-bromomethyl-1,3-dioxolane (7.63 mmol) in the presence of sodiumhydride (5.60 mmol) gave2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane (0.86 g) in 59%yield.

[0112] C. Preparation of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde.

[0113] Following the procedures described in the Example 1, Step B, thereaction of 2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane(2.98 mmol) with 1N hydrochloric acid gave3-cyclohexanecarbonyl-3-phenylpropionaldehyde as a crude product in 100%yield.

[0114] D. Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine.

[0115] Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39 mmol)and 2-methoxyphenylpiperazine (1.39 mmol) with sodiumtriacetoxyboranehydride (1.80 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(464 mg) in 79% yield. The oxalate salt was prepared as described above.

[0116] m.p.=149-151° C.;

[0117] MS (m/e): 420 (M⁺).

EXAMPLE 3

[0118]

1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazineoxalate

[0119] Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55 mmol)and 1-(2-pyridyl)piperazine (1.55 mmol) with sodiumtriacetoxyboranehydride (2.0 mmol) gave pure product1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(475 mg) in 78% yield. The oxalate salt was prepared as described above.

[0120] m.p.=185-187° C.;

[0121] MS (m/e): 391 (M⁺).

EXAMPLE 4

[0122]

1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazinedihydrochloride

[0123] Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02 mmol)and 1-(2-ethoxyphenyl)piperazine (1.13 mmol) with sodiumtriacetoxyboranehydride (1.33 mmol) gave pure product1-(2ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(270 mg) in 25% yield. To a solution of free base in methanol was addedrequired amount of hydrochloric acid solution in diethyl ether. Thesolvents were removed by reduced pressure, and the product was driedunder vacuum to give dihydrochloric acid salt.

[0124] m.p.=180-183° C.;

[0125] MS (m/e): 434 (M⁺).

EXAMPLE 5

[0126]

1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine oxalate

[0127] A. Preparation of 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane.

[0128] Following the procedures described in the Example 1, Step A, thereaction of 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (3.54 mmol) andiodomethane (10.62 mmol) in the presence of sodium hydride (4.25 mmol)gave 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane (0.60 g).

[0129] B. Preparation of 3-benzoyl-3-phenylbutyraldehyde.

[0130] Following the procedures described in the Example 1, Step B, thereaction of 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane (0.60 g) with3N hydrochloric acid gave 3-benzoyl-3-phenylbutyraldehyde as a crudeproduct (0.32 g).

[0131] C. Preparation of1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine.

[0132] Following the procedures described in the Example 1, Step C, thereaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and1-(2-methoxyphenyl)piperazine (0.23 g) with sodiumtriacetoxyboranehydride (0.33 g) gave pure product1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine (0.12 g).The oxalate salt was prepared as described above.

[0133] m.p.=192-193° C.;

[0134] MS (m/e): 428 (M⁺).

EXAMPLE 6

[0135]

1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazinedihydrochloride

[0136] Following the procedures described in the Example 1, Step C, thereaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol)and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with sodiumtriacetoxyboranehydride (3.28 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine(770 mg) in 70% yield. The dihydrochloric acid salt was prepared asdescribed above.

[0137] m.p.=193-194° C.;

[0138] MS (m/e): 434 (M⁺).

EXAMPLE 7

[0139]

1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazinedihydrochloride

[0140] Following the procedures described in the Example 1, Step C, thereaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol)and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodiumtriacetoxyboranehydride (1.77 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine(370 mg) in 67% yield. The dihydrochloric acid salt was prepared asdescribed above.

[0141] m.p.=210-212° C.;

[0142] MS (m/e): 406 (M⁺).

EXAMPLE 8

[0143]

1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazineoxalate

[0144] To a stirred solution of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(0.11 g, 0.20 mmol) in methylene chloride (10 mL) at −78° C. undernitrogen was added Dibal-H™ solution (0.89 mmol). The mixture wasstirred at −78° C. for 1 hour and then slowly warmed to room temperaturefor 16 hours. Workup followed by purification by flash chromatographygave pure1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazine(0.086 g) in 78% yield. The oxalate salt was prepared as describedabove.

[0145] m.p.=100-102° C.;

[0146] MS (m/e): 422 (M⁺).

EXAMPLE 9

[0147]

1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

[0148]

[0149] Preparation of 2-phenyl-1-cyclohexane-ethan-1-one.

[0150] Scheme III, step A: A 5 L reaction vessel was charged withtetrahydrofuran (1.05 L) under an atmosphere of nitrogen. The solutionwas cooled with an acetone/ice bath to about −5° C. Liquid dimethylamine(115.9 g, 2.57 mol) was then added through a teflon addition tube. Thecooling bath was removed and the solution was allowed to warm to about15-20° C. Methyl cyclohexanecarboxylate (341.7 g, 2.40 mol) was thenadded resulting in a tea-colored solution. Then benzylmagnesium chloride(2.52 L of a 2.0 M solution in THF, 246 mol) was slowly added at a rateto complete addition in about 1.8 to about 2.2 hours. A cooling bath wasapplied to maintain the temperature of the reaction mixture at about15-20° C. during the addition. After the benzylmagnesium chloridesolution was added, the resulting slurry was stirred at room temperaturefor about 1-2 hours. The reaction mixture was then cooled to less than0° C. Concentrated HCl (709.7 g, 7.2 mol) was combined with water (3.08L) and the solution was cooled to less than 5° C. The dilute acidmixture was added to a 22 L reaction vessel with an ice bath applied tothe vessel. The above-chilled reaction mixture was then slowly pouredinto the chilled dilute acid solution with stirring. An extreme exothermoccurs (Use Caution!). Addition rate of the reaction mixture should becontrolled to maintain the temperature of the quench solution below 45°C. After addition of the reaction mixture to the dilute acid solution,the quenched reaction mixture was cooled to room temperature and the pHwas adjusted to about 6.5 to 7.5 with a sufficient amount ofconcentrated HCl. The quenched reaction mixture was extracted with MTBE(1.71 L). The layers were separated and the organic layer was washedwith a water/MTBE mixture (1.03 L/1.37 L) followed by a second washingwith a water/MTBE mixture (1.03 L/1.03 L). The organic layers werecombined, washed with brine (683 mL), dried over anhydrous magnesiumsulfate (167 g), filtered and concentrated under vacuum. The crude oilwas dried under house vacuum for 5-16 hours to provide crude2-phenyl-1-cyclohexane-ethan-1-one (522.3 g). This crude material wasused in the next reaction without further purification.

[0151] Preparation of 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonylbutane.

[0152] Scheme III, step B; 2-Phenyl-1-cyclohexane-ethan-1-one (8.26 g,40.8 mmol) was combined with DMSO (45 mL) in a 3-necked, 250 mL roundbottom flask equipped with a magnetic stir bar, thermocouple-digitalthermometer unit and an addition funnel. To the stirring solution wasadded potassium tert-butoxide (5.04 g, 44.9 mmol). A 16° C. exotherm wasobserved and the yellow solution became dark brown. The reaction mixturewas stirred for an additional 15 minutes after addition was complete,and then bromoacetaldehyde diethyl acetal (8.26 g, 41.9 mmol) was addeddropwise via the addition funnel over approximately 10 minutes. Thereaction mixture was then heated at 50° C. for 2 to 2.5 hours duringwhich the reaction mixture became yellow. The reaction mixture was thencooled with an ice/water bath to about 9.5° C. and potassiumtert-butoxide (10.07 g, 89.7 mmol) was added resulting in an exothermicreaction and change in color from yellow to brown with the cooling bathstill in place, the reaction mixture was stirred for an additional 15minutes followed by dropwise addition of iodomethane (10.26 g, 72.3mmol, neat). The temperature of the reaction mixture was maintained ator below 21° C. Any exotherm during the iodomethane addition should bemaintained below 41-43° C., which is the boiling point of iodomethane.After addition was complete, the reaction mixture was allowed to stirfor 1 to 4 hours at room temperature. The reaction mixture was thenpartitioned between MTBE (100 mL) and water (100 mL). The organic phasewas washed with water (3×50 mL), brine (50 mL), dried over anhydrousmagnesium sulfate, suction filtered and concentrated under vacuum toprovide crude 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane (13.6g) as a yellow oil. This crude material was used in the next reactionwithout further purification.

[0153] Preparation of 1-cyclohexyl-2-phenyl-butan-1-one-4-al.

[0154] Scheme III, step C;1,1-Diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane (74.4 g, 224 mmol)was dissolved in acetone (800 mL) followed by addition of 3.0 N HCl (800mL). The reaction mixture was stirred for one hour at room temperature.It was then concentrated under vacuum to less than ½ its original volumeand then extracted with methylene chloride (800 mL). The organic extractwas then washed with brine (300 mL), dried over anhydrous magnesiumsulfate, suction filtered and concentrated under vacuum to provide crude3-phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g). Alternatively, thedried and filtered methylene chloride solution can be used directly inthe next step without concentration.

[0155] Preparation of the Final Title Compound,1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

[0156] Scheme III, step D; 3-Phenyl-3-cyclohexanecarbonylbutan-1-al(57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL)followed by addition of 1-(2-methoxyphenyl)piperazine hydrochloride(56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to turnthe slurry into a solution. To the stirred solution, sodiumtriacetoxyborohydride (60.3 g, 284 mmol) was slowly added. A slightexotherm resulted and a slurry was produced. The reaction mixture wasstirred for an additional 3 hours at room temperature. The reaction wasthen quenched by addition of 2.0 N sodium hydroxide (1050 mL) producinga pH of about 10 for the quenched reaction mixture. The mixture was thenextracted with methylene chloride (2 times, 1L and 300 mL). The organicextracts were combined, washed successively with 1.0 N HCl (600 mL), 1.0N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum to provide thefinal title compound as a thick oil;

[0157] UV (MeOH): λ_(max)=243 nm, ε₂₄₃=7110; λ_(max)=281 nm, ε₂₈₁=3200

[0158] IR (CDCl₃, cm⁻¹) 2937, 2856, 2836, 1698, 1499, 1451, 1377, 1316,1242, 1029

[0159]¹H NMR (300 MHz, DMSO) δ 7.75 (2H, m), 7.55 (2H, m), 6.93 (3H, m),6.85 (2H, m), 3.75 (3H, s), 2.90 (4H, m), 2.43 (4H, m), 2.08 (5H, m),1.5 (10H, m), 1.05 (3H, m)

[0160]¹³C NMR (300 MHz, DMSO) δ 214.18, 151.94, 141.25, 141.23, 128.45,126.85, 126.74, 122.22, 120.79, 117.81, 111.97, 55.28, 54.54, 53.67,53.13, 50.01, 45.30, 33.75, 30.44, 30.12, 25.21, 24.98, 24.93, 19.94.

[0161] Anal. Calcd for C₂₈H₃₈N₂O₂: C, 77.38; H, 8.81; N, 6.45. Found: C,76.44; H, 8.89; N, 6.01.

[0162] Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemaleate.

[0163]1-(2-Methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(prepared directly above) was dissolved in warm methanol (50 mL)followed by addition of maleic acid (26.8 g) and MTBE (200 mL). Thismixture was concentrated to a paste and then redissolved by addition ofmethanol (approximately 15 mL) and MTBE (200 mL). The mixture was seededand an additional amount of MTBE (300 mL) was added once crystallizationwas initiated. The mixture was suction filtered, and the solid rinsedwith MTBE and vacuum dried for 5 hours at 40° C. to provide the titlecompound (122 g).

[0164] In addition, one of ordinary skill in the art could prepare thetitle compound,1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine,in a manner analogous to the procedures described above, from3-cyclohexanecarbonyl-3-phenylbutyraldehyde and1-(2-methoxyphenyl)piperazine as described generally in Scheme V.

[0165] Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine2HCl.

[0166] The title compound is prepared by one of ordinary skill in theart, in a manner analogous to preparation of the above maleate salt,from the free base and hydrochloric acid to provide a white solid; mp(DSC)=192.81° C.

[0167] Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazineand(−)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

[0168] Scheme III, step E:

[0169] Materials:

[0170] Chiralpak AD Bulk packing, 20 micron

[0171] Acetonitrile

[0172] 3A alcohol

[0173] Prochrom 8 cm column

[0174] Prochrom LC-80 system/collection system

[0175] Column Preparation: A ProChem LC-80 automated system with an 8×19cm Prochrom column (ProChem, 5622 West 73^(rd) Street, Indianapolis,Ind. 46278) is slurry packed using approximately 500 g Chiralpak AD(Chiral Technologies, 730 Springdale Drive, Exton, Pa. 19341) inpropanol (1 L). An eluent containing approximately 5% 3A alcohol inacetonitrile was prepared. Column flow rate was 155 mL/min and thedetector was set at 280 nm. The racemic1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(methyl)-3-(phenyl)propyl]piperazine(25 g) was dissolved in acetonitrile (50 mL). Approximately 3 g of thissolution was weighed into a flask and diluted with acetonitrile (50 mL).This solution was then pumped onto the column to begin separation of the(+) and (−) enantiomers of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.Fractions were then collected with the (−) enantiomer eluting first.Approximate total cycle time is 15 minutes.

[0176] The enantiomeric excess of the two separated isomers wasdetermined under the following conditions:

[0177] Column: 46×15 cm Chiralcel OH—H

[0178] Eluent: 3% ethanol in Heptane containing 0.2% dimethylamine

[0179] Flow rate: 0.6 mL/min

[0180] Temperature: ambient

[0181] uv: 280 nm

[0182] % ee for the (−) enantiomer 96.4%.

[0183] % ee for the (+) enantiomer 96.6%.

[0184] Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinedihydrochloride.

[0185] Scheme III, step F:(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(15.0 g, 34.5 mmol, prepared above) was diluted with methanol (40 mL).To this solution was added HCl (9.58 g of a 26.3% solution in methanol,69.0 mmol). The mixture began to form gelatinous-looking crystals andset up solid within minutes. To this mixture was added with vigorousstirring, diethyl ether (100 mL). The white solid was collected bysuction filtration and then dried under vacuum at 45° C. for two days toprovide the title compound (13.4 g, 76%) as a white solid; mp(DSC)=195.58° C.

[0186] IR (CDCl₃, cm⁻¹) 2976, 2939, 1700, 1502, 1462, 1451, 1267, 1243,1021;

[0187]¹H NMR (300 MHz, DMSO) δ 7.40 (2H, m), 73.1 (3H, m) 7.03 (3H, M)6.90 (1H, m) 3.78 (3H, s) 3.49 (4H, m) 3.16 (5H, m) 2.64 (1H, m) 2.40(3H, m) 1.56 (3H, s) 1.46 (4H, m) 1.11 (5H, m) 0.86 (1H, m);

[0188]¹³C NMR (300 MHz, DMSO) δ 213.46, 151.84, 139.56, 138.12, 128.72,127.37, 126.86, 124.29, 120.85, 118.71, 112.29, 55.48, 54.06, 52.20,50.78, 50.57, 46.93, 45.14, 30.31, 30.16, 25.15, 24.91, 24.89, 19.15;

[0189] HRMS calcd for C₂₈H₃₉N₂O₂ (MH⁺) 435.3012, found 435.3018.

[0190] [α]²⁵ _(D)=+76.53° (c=1, MeOH), ee 99.3% (Chiral HPLC).

[0191] Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrochloride.

[0192] Scheme III, step F:(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(6.05 g, 13.9 mmol) was diluted with MTBE (120 mL) followed by additionof HCl (2.2 M solution in isopropanol, 6.3 mL, 13.9 mmol, prepared from0.80 g of HCl gas in 10 mL of isopropanol). The mixture formed anoil/solid mixture which upon further stirring yielded a uniformlycrystalline material. The mixture was suction-filtered and rinsed withMTBE to provide a white solid which was dried under vacuum at 45° C.(5.74 g, 96.2% ee).

[0193](+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrochloride can be prepared in an analogous manner as above froman equivalent of concentrated aqueous HCl in place of the gaseous HCl.

[0194] Alternative Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

[0195] Preparation of 1-Cyclohexyl-2-phenylpropanol.

[0196] Scheme IV, step A: To a solution of cyclohexylmagnesium chloride(50 mmol) in 25 mL of Et₂O and 40 mL of THF at −5° C. was added asolution of 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF.The reaction mixture exothermed to 5° C. After stirring at roomtemperature for 75 min, the solution was poured onto ice cold 1 N HCl,extracted with toluene, dried over MgSO₄, and concentrated to give thetitle compound as a colorless oil (6.15 g, 70%): ¹H NMR (d⁶-DMSO): δ7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51(br s, 1H, —OH), 3.23-3.33 (m, 1H, R₂CHOH), 2.78 (dq, J=7.0 Hz, J=7.1Hz, 1H, —CH(CH₃)Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J=6.9Hz, 3H, —CH(CH ₃)Ph), 0.88-1.18 (m, 5H, cyclohexyl CH).

[0197] Preparation of Cyclohexyl 1-phenylethyl ketone.

[0198] Scheme IV, step B: DMSO (118 mL, 1.6674 mol) was added dropwiseto a solution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanolin 1737 mL of CH₂Cl₂ (cooled in a wet ice acetone bath). After 29 min,147.93 g (1.0422 mol) of P₂O₅ was added. After 11 min, the cooling bathwas removed. An aliquot quenched with Et₃N showed complete reactionwithin 3 h at RT. The reaction mixture was cooled in a wet ice acetonebath. Et₃N (282 mL, 2.0265 mol) was added dropwise to the cooledreaction mixture over a 30 min period. The cooling bath was removed andthe mixture was stirred overnight at RT. The reaction mixture wasquenched by dropwise addition of 500 mL of 3 N HCl (aq) (pH=0). Aftershaking in separatory funnel, the aqueous phase was removed. The organicphase was washed with 500 mL of 3 N HCl (aq) (pH=0), washed twice with 1L of 10% K₂CO₃ (aq) (pH=12;12), washed three times with 500 mL of NaOCl(aq) solution, washed with 1L of water, washed with 1 L of 25% NaCl(aq), dried over MgSO₄, gravity filtered and concentrated under vacuumwith dry ice trap to collect Me₂S. An amber oil of the title compound(107.01 g, 85.437%) was obtained;

[0199]¹H NMR (d⁶-DMSO) δ 7.30-7.37 (m, 2H, phenyl CH), 7.21-7.28 (m, 3H,phenyl CH), 4.08 (q, J=6.9 Hz, 1H, —CH(CH₃)Ph), 2.40-2.49 (m, 1H,cyclohexyl CH), 1.82-1.84 (m, 1H, cyclohexyl —CH₂), 1.67-1.69 (m, 1H,cyclohexyl —CH₂), 1.52-1.63 (m, 1H, cyclohexyl —CH₂), 1.34-1.43 (m, 1H,cyclohexyl —CH₂), 1.26 (d, J=6.9 Hz, 3H, —CH(CH ₃)Ph), 1.01-1.24 (m, 4H,cyclohexyl —CH₂).

[0200] Preparation of 2-phenyl-2-methyl-4-pentenoyl cyclohexane.

[0201] Scheme IV, step C; A solution of 31.39 g (0.2797 mol) of t-BuOKin 100 mL of THF was added dropwise to a solution of 55.00 g (0.2543mol) of cyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052 mol) ofallyl bromide in 136 mL of THF (cooled in a wet ice acetone bath). THFwashings (16 mL) were added to the reaction mixture. The cooling bathwas removed after addition. After reaction completion (2 h), thereaction mixture was quenched with 300 mL of 1 N HCl (pH=0) andextracted with 300 mL of heptane. The heptane extract was washed with10% NaHCO₃ (aq) (pH=9), dried over MgSO₄, gravity filtered andconcentrated under vacuum to afford 59.70 g (91.58%) of title compoundas an amber oil: ¹H NMR (d⁶-DMSO): δ 7.32-7.42 (m, 2H, phenyl CH),7.24-7.31 (m, 3H, phenyl CH), 5.34-5.47 (m, 1H, —CH═CH₂), 5.02 (dd,J=17.1 Hz, J=2.1 Hz, 1H, —CH═CH—H (trans)), 4.97 (ddd, J=10.2 Hz, J=2.2Hz, J=1.0 Hz, 1H, —CH═CH—H (cis, W-coupling)), 2.66 (ddd, J=14.2 Hz,J=6.9 Hz, J=1.0 Hz, 1H, —CH ₂CH═CH₂), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz,J=1.0 Hz, 1H, —CH ₂CH═CH₂), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48-1.69(m, 4H, cyclohexyl —CH ₂), 1.46 (s, , 3H, —CH(CH ₃)Ph), 1.36-1.44 (m,1H, cyclohexyl —CH ₂), 0.82-1.36 (m, 5H, cyclohexyl —CH ₂).

[0202] Preparation of 4-Cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.

[0203] Scheme IV, step D: Ozone was bubbled through a cloudy mixture of56.50 g (0.2204 mol) of 2-phenyl-2-methyl-4-pentenoyl cyclohexane and asmall amount (˜10 mg) of Sudan III in 220 mL of MeOH (cooled in a dryice acetone bath at −20° C.) for 4 h until pink color turned to paleyellow color. After all of the olefin was consumed, Me₂S (50 mL) wasadded to reaction mixture. The cooling bath was removed. The exothermrose to 38° C. and mixture was cooled in cooling bath until there was noexotherm. Then the cooling bath was removed and the mixture was stirredovernight. The reaction solution was concentrated under vacuum with dryice trap to collect excess Me₂S to afford 83.65 g of crude4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal as apink oil:

[0204]¹H NMR (d⁶-DMSO): δ 7.34-7.39 (m, 2H, phenyl CH), 7.24-7.30 (m,3H, phenyl CH), 3.99 (dd, J=4.2 Hz, J=5.9 Hz, 1H, CH(OCH₃)₂), 3.14 (s,3H, CH(OCH ₃)₂), 3.06 (s, 3H, CH(OCH ₃)₂), 2.34-2.43 (m, 1H, cyclohexylCH), 2.10-2.20 (m, 2H, —CH ₂CH(OCH ₃)₂), 1.55-1.67 (m, 1H, cyclohexyl—CH ₂), 1.53 (s, 3H, R₂C(CH₃)Ph), 0.80-1.52 (m, 9H, cyclohexyl —CH ₂).

[0205] To a solution of 82.65 g (66.29 g, 0.2177 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reactioncompletion (2 h), the mixture was concentrated to 426.5 g (or ⅓ volume)of residue (RT-40° C.). The residue contained mostly water (pH=0) andwas extracted twice with 300 mL of MTBE. The MTBE extract was washedwith 300 mL of 25% NaCl (aq), dried over MgSO₄, gravity filtered andconcentrated to afford 54.92 g (97.65%) of title compound as a pink oil:¹H NMR (d⁶-DMSO): δ 9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H,phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz,1H, CH ₂CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH ₂CHO), 2.41-2.49 (m,1H, cyclohexyl CH), 1.72 (s, 3H, R₂C(CH₃)Ph), 0.85-1.66 (m, 10H,cyclohexyl —CH ₂).

[0206] Preparation of Final Title Compound1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

[0207] Scheme IV, step E: To a slurry of 13.72 g (0.05310 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde and 11.57 g (0.05058mol) of 1-(2′-methoxyphenyl)piperazine hydrochloride in 391 mL of CH₂Cl₂was added 9.7 mL of AcOH to make the reaction mixture homogeneous. Tothe reaction solution was added slowly 14.63 g (0.06904 mol) ofNaBH(OAc)₃. After stirring over 4 days (reaction should be completewithin 2-5 h), 200 mL of 1N HCl (aq) was added to quench reactionmixture (pH=1). The mixture was extracted with 200 mL of CH₂Cl₂. TheCH₂Cl₂ extract was washed again with 200 mL of 1N HCl (aq) (pH=1). BothHCl (aq) washes were combined and saved. The organic extract was washedwith 200 mL of 1N NaOH (aq) (pH=14). An emulsion formed and was brokenup by addition of 100 mL of water and 100 mL of MTBE. The organic phasewas washed again with 200 mL of 1N NaOH (aq) (pH=14) and washed with 200mL of 25% NaCl (aq), dried over MgSO₄, gravity filtered and concentratedto afford 22.74 g of crude title compound as an amber oil. HPLC analysisagainst pure standard showed that crude product oil has 13.66 g (61.71%)of title compound.

[0208] To the combined HCl wash was added 28.44 g of NaOH (s) to makemixture basic (pH=14). The cloudy mixture was extracted twice with 100mL of CH₂Cl₂. The CH₂Cl₂ extracts were combined, washed with 25% NaCl(aq), dried over MgSO₄, gravity filtered and concentrated to afford 1.86g of amber oil residue that contained 0.096 g (total=62.15%) of titlecompound and 1.05 g (10.8% recovery) of 1-(2′-methoxyphenyl)piperazine.

[0209]¹H NMR (d⁶-DMSO): δ 7.35-7.43 (m, 2H, phenyl CH), 7.26-7.32 (m,3H, phenyl CH), 6.89-6.96 (m, 2H, phenyl CH), 6.83-6.88 (m, 2H, phenylCH), 3.76 (s, 3H, OCH ₃), 2.80-3.03 (m, 4H, piperazine CH ₂), 2.34-2.49(m, 4H, piperazine CH ₂), 1.91-2.24 (m, 4H), 1.52-1.62 (m, 2H,cyclohexyl CH ₂), 1.51 (s, 3H, R₂C(CH₃)Ph), 1.34-1.48 (m, 2H, cyclohexyl—CH ₂), 1.13-1.27 (m, 4H, cyclohexyl —CH ₂), 1.00-1.10 (m, 2H,cyclohexyl —CH ₂), 0.83-1.00 (m, 1H, cyclohexyl —CH ₂).

[0210] Alternative Preparation of Final Title Compound.

[0211] Preparation of Enamine.

[0212] Scheme V, step A: To a solution of 25.00 g (0.1093 mol) of1-(2′-methoxyphenyl)piperazine hydrochloride in 42 mL of water was added14.5 mL (0.109 mol) of concentrated (29.4%) NH₄OH (aq) (pH=9). Themixture was extracted twice with 250 mL of 1:1 (v/v) of THF:toluene. Theorganic extracts were combined, dried over MgSO₄, gravity filtered andconcentrated to afford 20.17 g (96.00%) of1-(2′-methoxyphenyl)piperazine as a pale green oil: ¹H NMR (d⁶-DMSO): d6.90-6.97 (m, 2H, phenyl CH), 6.83-6.90 (m, 3H, phenyl CH), 3.77 (s, 3H,OCH₃), 2.77-2.91 (m, 8H, piperazine CH ₂), 2.49-2.53 (m, 1H, NH). Asolution of 9.55 g (0.0370 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde in 10 mL of iPrOAc wasadded to 6.77 g (0.0352 mol) of neat 1-(2′-methoxyphenyl)piperazine. Themixture turned turbid, and then turned to a solid mass when 10 mL ofiPrOAc was added. The solid was slurried with 45 mL of iPrOAc. After 1.5h, reaction was complete. The solid was vacuum filtered and washed with10 mL of iPrOAc and air dried to afford 9.81 g (64.4%) of pure enamineas an off-white powder. The filtrate was concentrated to afford 6.40 gof crude enamine;

[0213]¹H NMR (d⁶-DMSO): δ 7.31-7.43 (m, 2H, phenyl CH), 7.20-7.31 (m,3H, phenyl CH), 6.82-7.04 (m, 4H, phenyl CH), 6.06 (d, J=14.2 Hz, 1H,CR₃CH═CHNR₂ (trans)), 4.98 (d, J=14.2 Hz, 1H, CR₃CH═CH NR₂(trans)), 3.80(s, 3H, OCH ₃), 2.93-3.15 (m, 8H, piperazine CH ₂), 2.38-2.49 (m, 1H,cyclohexyl CH), 1.59-1.72 (m, 2H, cyclohexyl CH ₂), 1.47-1.59 (m, 2H,cyclohexyl —CH ₂), 1.40 (s, 3H, R₂C(CH₃)Ph), 1.21-1.34 (m, 3H,cyclohexyl —CH ₂), 1.03-1.21 (m, 2H, cyclohexyl —CH ₂), 0.83-1.03 (m,1H, cyclohexyl —CH ₂).

[0214] Preparation of Final Title Compound.

[0215] Scheme V, step B: To 5.35 g (0.00101 mol) of 5% Pd/C in a 500 mLParr bottle chilled in an ice bath was added 8.68 g (0.0201 mol) ofabove-formed enamine. To the solid mixture was added 40 mL of IPA cooledin a freezer (−22° C.). H₂ was introduced at 50 psi and mixture wasshaken for 2 day at RT to complete reaction. The black slurry was vacuumfiltered and concentrated to afford 8.70 g of a colorless oil. The Pd/Ccatalyst was washed with 50 mL of IPA with stirring. The black slurrywas vacuum filtered. The filtrate was combined with 8.70 g of residueand concentrated to afford 10.03 g of the final title compound as acolorless oil.

[0216] Additional compounds included with the scope of the presentinvention, which can be prepared by one of ordinary skill in the art ina manner analogous to the procedures described above, are as follows:

[0217] 10)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinedihydrobromide;

[0218] 11)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrobromide;

[0219] 12)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinesuccinate, 1:1;

[0220] 13)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinesuccinate, 2:1;

[0221] 14)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinephosphate;

[0222] 15)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazined-tartrate;

[0223] 16)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine1-tartrate;

[0224] 17)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemaleate;

[0225] Serotonin 1A Receptor Activity

[0226] The compounds of the present invention are selective antagonistsat the serotonin 1A receptor. Previously known compounds with 1Areceptor activity typically have the disadvantage of possessing othercentral nervous system activities as well. It is now well understood bypharmacologists and physicians that pharmaceuticals which have a singlephysiological activity, or which are much more active in the desiredactivity than in their other activities, are much more desirable fortherapy than are compounds (pindolol for example) which have multipleactivities at about the same dose.

[0227] Many other known serotonin receptor 1A antagonists typically haveα-adrenergic, β-adrenergic or dopamine-2 activity as well, and aretherefore nonselective for 1A activity.

[0228] The 5-HT_(1A) receptor binding potency of the present compoundshas been measured by a modification of the binding assay described byTaylor, et al. (J. Pharmacol. Exp. Ther., 236, 118-125, 1986); and Wong,et al., Pharm. Biochem. Behav., 46, 173-77 (1993). Membranes for thebinding assay were prepared from male Sprague-Dawley rats. (150-250 g).The animals were killed by decapitation, and the brains were rapidlychilled and dissected to obtain the hippocampi. Membranes from thehippocampi were either prepared that day, or the hippocampi were storedfrozen (−70°) until the day of preparation. The membranes were preparedby homogenizing the tissue in 40 volumes of ice-cold Tris-Hydrochloricacid buffer (50 mM, pH 7.4 at 22°) using a homogenizer for 15 seconds,and the homogenate was centrifuged at 39800×g for 10 minutes. Theresulting pellet was then resuspended in the same buffer, and thecentrifugation and resuspension process was repeated three additionaltimes to wash the membranes. Between the second and third washes theresuspended membranes were incubated for 10 minutes at 37° to facilitatethe removal of endogenous ligands. The final pellet was resuspended in67 mM Tris-Hydrochloric acid, pH 7.4, to a concentration of 2 mg oftissue original wet weight/200 μl. This homogenate was stored frozen(−70°) until the day of the binding assay. Each tube for the bindingassay had a final volume of 800 μl and contained the following:Tris-Hydrochloric acid (50 mM), pargyline (10 μM), CaCl₂ (3 mM),[³H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs of interest,and membrane resuspension equivalent to 2 mg of original tissue wetweight, for a final pH of 7.4. The assay tubes were incubated for either10 minutes or 15 minutes at 37°, and the contents were then rapidlyfiltered through GF/B filters (pretreated with 0.5% polyethylenimine),followed by four one-ml washes with ice-cold buffer. The radioactivitytrapped by the filters was quantitated by liquid scintillationspectrometry, and specific [³H]8-OH-DPAT binding to the 5-HT_(1A) siteswas defined as the difference between [³H]8-OH-DPAT bound in thepresence and absence of 10 μM 5-HT.

[0229] IC₅₀ values, i.e., the concentration required to inhibit 50% ofthe binding, were determined from 12-point competition curves usingnonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, Ill.). IC₅₀ valueswere converted to K_(i) values using the Cheng-Prusoff equation(Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments wereperformed in triplicate.

[0230] Additional binding assays of some of the present compounds havebeen carried out by an assay method which uses a cloned cell line whichexpresses the serotonin 1A receptor, rather than the hippocampalmembranes. Such cloned cell lines have been described by Fargin, et al.,J.Bio. Chem., 264, 14848-14852 (1989), Aune, et al., J. Immunology, 151,1175-1183 (1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 346, 127-137 (1992). Results from the cell line assay aresubstantially in agreement with results from the hippocampal membraneassay. 5HT_(1a) antagonist, in vivo tests

[0231] a) 5HT_(1a) Antagonism Subcutaneous Test

[0232] Compounds were tested over a range of subcutaneous doses foractivity in blocking the 8-OH-DPAT induced behaviors and hypothermia.Lower lip retraction (LLR) and flat body posture (FBP) were recorded inmale Sprague Dawley rats (˜250 grams from Harlan Sprague Dawley). BothLLR and FBP were measured on a scale of 0-3 (Wolff et al, 1997). In theLLR behavioral assay, “0” indicated normal lip position; “1” indicated aslight separation of the lips; “2” indicated that the lips were openwith some teeth visible; “3” indicated that the lips were fully openwith all the front teeth exposed. In the FBP assay, a score of “0”indicated normal body posture; “1” indicated that the stomach was on thefloor with the back in its normal rounded position; “2” indicated thatthe stomach was on the floor with the back straightened and rising fromthe shoulders to the hips; “3” indicated that the stomach was pressedinto the floor and the back was flattened with the shoulders and hipseven. Core body temperature was recorded by rectal probe inserted 5.0 cmimmediately after the behavioral measures. Rats were injectedsubcutaneous with compound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutesbefore scoring and the 8-OH-DPAT (0.1 mg/kg subcutaneous) was injected20 minutes before scoring.

[0233] b) 5HT_(1a) Agonist Subcutaneous Test

[0234] The compounds were also tested at a high dose of 10 mg/kgsubcutaneous alone to see if they induced 5HT_(1a) agonist-likehypothermia.

[0235] The potent serotonin 1A receptor activity of the presentcompounds gives them a number of pharmaceutical and therapeuticapplications. One of those applications is a method of assisting peoplewho are dependent on the use of tobacco or nicotine to break the habit.

[0236] Tobacco or Nicotine Withdrawal

[0237] It is well known that the chronic administration of nicotineresults in tolerance and, eventually, dependence. The use of tobacco hasbecome extremely widespread in all countries, despite the well knownadverse effects of the use of tobacco in all its forms. Thus, it isclear that tobacco use is extremely habit-forming, if not addictive, andthat its use provides sensations to the user which are pleasant andwelcome, even though the user is fully aware of the drastic long termill effects of its use.

[0238] Rather recently, vigorous campaigns against the use of tobaccohave taken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

[0239] At the present time, probably the most widely used therapy toassist the cessation of tobacco use is nicotine replacement, by the useof nicotine chewing gum or nicotine-providing transdermal patches. It iswidely known, however, that nicotine replacement is less effectivewithout habit-modifying psychological treatment and training.

[0240] The method of the present invention is broadly useful inassisting persons who want to cease or reduce their use of tobacco ornicotine. Most commonly, the form of tobacco use is smoking, mostcommonly the smoking of cigarettes. The present invention is alsohelpful, however, in assisting in breaking the habit of all types oftobacco smoking, as well as the use of snuff, chewing tobacco, etc. Thepresent method is also helpful to those who have replaced, or partiallyreplaced, their use of tobacco with the use of nicotine replacementtherapy. Thus, such patients can be assisted to reduce and eveneliminate entirely their dependence on nicotine in all forms.

[0241] It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict patientswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, lightheadedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the patient's use of tobacco or nicotine is adesired result of the present invention and an important aspect of it.

[0242] The present invention is carried out by administering aneffective amount of a compound of Formula I or formula Ia to a patientwho is in need of or carrying out a reduction or cessation of tobacco ornicotine use.

[0243] As used herein, the term “patient” refers to a warm-bloodedanimal, such as a mammal. Included within the term “patient” are humans,dogs, rats, mice and the like. It is understood that the preferredpatient is a human.

[0244] An effective amount of a compound of Formula I or formula Ia, isthe amount, or dose, of the compound which provides the desired effectin the patient under diagnosis or treatment. The dose of compound ofFormula I or formula Ia to be administered, is effective over a widedosage range, in general, it is from about 1 to about 200 mg/day; asusual, the daily dose may be administered in a single bolus, or individed doses, depending on the judgment of the physician in charge ofthe case. A more preferred range of doses is from about 5 to about 100mg/day; other dosage ranges which may be preferred in certaincircumstances are from about 10 to about 50 mg/day; from about 5 toabout 50 mg/day; from about 10 to about 25 mg/day; and a particularlypreferred range is from about 20 to about 25 mg/day. It will beunderstood that the dose for a given patient is always to be set by thejudgment of the attending physician, and that the dose is subject tomodification based on the size of the patient, the lean or fat nature ofthe patient, the characteristics of the particular compound chosen, theintensity of the patient's tobacco habit, the intensity of the patient'swithdrawal symptoms, and psychological factors which may affect thepatient's physiological responses.

[0245] The effect of the compounds in alleviating the symptoms ofnicotine withdrawal was evaluated in rats by an auditory startle test,which was carried out as follows.

[0246] Procedures for Nicotine Withdrawal Studies

[0247] Animals: Male Long Evans rats were individually housed in acontrolled environment on a 12 hour light-dark cycle and were given freeaccess to food (Purina Rodent Chow) and water. All treatment groupscontained 8-10 rats.

[0248] Chronic Nicotine Treatment: Rats were anesthetized with halothaneand Alzet™ osmotic minipumps (Alza Corporation, Palo Alto, Calif., Model2ML2) were implanted subcutaneously. Nicotine ditartrate was dissolvedin physiological saline. Pumps were filled with either nicotineditartrate (6 mg/kg base/day) or physiological saline. Twelve daysfollowing implantation of pumps, rats were anesthetized with halothaneand the pumps were removed.

[0249] Auditory Startle Response: The sensory motor reactions [auditorystartle response (peak amplitude Vmax)] of individual rats was recordedusing San Diego Instruments startle chambers (San Diego, Calif.).Startle sessions consisted of a 5-minute adaptation period at abackground noise level of 70±3 dBA immediately followed by 25presentations of auditory stimuli (120±2 dBA noise, 50 ms duration)presented at 8-second intervals. Peak startle amplitudes were thenaveraged for all 25 presentations of stimuli for each session. Auditorystartle responding was evaluated daily at 24 hour intervals on days 1-4following nicotine withdrawal.

[0250] Combination with Reuptake Inhibitors

[0251] A further application of the compounds of Formula I or formula Iais their use in combination with a serotonin reuptake inhibitor tofurther potentiate the action of those drugs by increasing theavailability of serotonin, as well as norepinephrine and dopamine, inthe brain of patients to whom the drug combination is administered.Typical and appropriate serotonin reuptake inhibitors (SRI) arefluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,fluvoxamine and paroxetine. Accordingly, the present invention providesa method for potentiating the action of a serotonin reuptake inhibitor,particularly one of the group consisting of fluoxetine, duloxetine,venlafaxine, milnacipran, citalopram, fluvoxamine and paroxetine, inincreasing the availability of serotonin, norepinephrine and dopamine inthe brain, comprising administering said serotonin reuptake inhibitor incombination with a compound of Formula I or formula Ia. The inventionalso provides pharmaceutical compositions which comprise a serotoninreuptake inhibitor in combination with a compound of Formula I orformula Ia, and a method of treating a pathological condition which iscreated by or is dependent upon decreased availability of serotonin,dopamine or norepinephrine, which method comprises administering thesame adjunctive therapy to a patient in need of such treatment.

[0252] Fluoxetine,N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is marketedin the hydrochloride salt form, and as the racemic mixture of its twoenantiomers. U.S. Pat. No. 4,314,081 is an early reference on thecompound. Robertson, et al., J. Med. Chem., 31, 1412 (1988), taught theseparation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word “fluoxetine” will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers.

[0253] Duloxetine,N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usuallyadministered as the hydrochloride salt and is the (+) enantiomer. It wasfirst taught by U.S. Pat. No. 4,956,388, which shows its high potency.The word “duloxetine” will be used here to refer to any acid additionsalt or the free base of the molecule.

[0254] Venlafaxine is known in the literature, and its method ofsynthesis and its activity as an inhibitor of serotonin andnorepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxineis identified as compound A in that patent.

[0255] Milnacipran(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught byU.S. Pat. No. 4,478,836, which prepared milnacipran as its Example 4.The patent describes its compounds as antidepressants. Moret, et al.,Neuropharmacology 24, 1211-19 (1985), describe its pharmacologicalactivities.

[0256] Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol., 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol., 2, 225 (1987), and Timmerman, et al., ibid., 239.

[0257] Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanoneO-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen, et al., Brit.J. Pharmacol., 60, 505 (1977); and De Wilde, et al., J. AffectiveDisord., 4, 249 (1982); and Benfield, et al., Drugs, 32, 313 (1986).

[0258] Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol., 47, 351 (1978);Hassan, et al., Brit. J. Clin. Pharmacol., 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand., 71, 249 (1985); and Battegay, et al.,Neuropsychobiology, 13, 31 (1985).

[0259] All of the U.S. patents which have been mentioned above inconnection with compounds used in the present invention are incorporatedherein by reference.

[0260] In general, combinations and methods of treatment usingfluoxetine or duloxetine as the SRI are preferred.

[0261] It will be understood by the skilled reader that all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals described aboveas salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

[0262] The dosages of the drugs used in the present combination must, inthe final analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferreddosages, are provided. Dosage guidelines for some of the drugs willfirst be given separately; in order to create a guideline for anydesired combination, one would choose the guidelines for each of thecomponent drugs.

[0263] Fluoxetine: from about 1 to about 80 mg, once/day; preferred,from about 10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

[0264] Duloxetine: from about 1 to about 30 mg once/day; preferred, fromabout 5 to about 20 mg once/day;

[0265] Venlafaxine: from about 10 to about 150 mg once-thrice/day;preferred, from about 25 to about 125 mg thrice/day;

[0266] Milnacipran: from about 10 to about 100 mg once-twice/day;preferred, from about 25 to about 50 mg twice/day;

[0267] Citalopram: from about 5 to about 50 mg once/day; preferred, fromabout 10 to about 30 mg once/day;

[0268] Fluvoxamine: from about 20 to about 500 mg once/day; preferred,from about 50 to about 300 mg once/day;

[0269] Paroxetine: from about 5 to about 100 mg once/day; preferred,from about 50 to about 300 mg once/day.

[0270] In more general terms, one would create a combination of thepresent invention by choosing a dosage of SRI according to the spirit ofthe above guideline, and choosing a dosage of the compound of Formula Ior formula Ia in the ranges taught above.

[0271] The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of Formula I or formula Iain any manner which provides effective levels of the two compounds inthe body at the same time. All of the compounds concerned are orallyavailable and are normally administered orally, and so oraladministration of the adjunctive combination is preferred. They may beadministered together, in a single dosage form, or may be administeredseparately.

[0272] However, oral administration is not the only route or even theonly preferred route. For example, transdermal administration may bevery desirable for patients who are forgetful or petulant about takingoral medicine. One of the drugs may be administered by one route, suchas oral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

[0273] It is particularly preferred, however, for the adjunctivecombination to be administered as a single pharmaceutical composition,and so pharmaceutical compositions incorporating both a SRI and acompound of Formula I or formula Ia are important embodiments of thepresent invention. Such compositions may take any physical form which ispharmaceutically acceptable, but orally usable pharmaceuticalcompositions are particularly preferred. Such adjunctive pharmaceuticalcompositions contain an effective amount of each of the compounds, whicheffective amount is related to the daily dose of the compounds to beadministered. Each adjunctive dosage unit may contain the daily doses ofboth compounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

[0274] As stated above, the benefit of the adjunctive therapy is itsability to augment the increase in availability of serotonin,norepinephrine and dopamine caused by the SRI compounds, resulting inimproved activity in treating the various conditions described below indetail. The increase in availability of serotonin is particularlyimportant and is a preferred aspect of the invention. Further, theinvention provides a more rapid onset of action than is usually providedby treatment with the SRI alone.

[0275] Preferred pathological conditions to be treated by the presentmethod of adjunctive therapy include depression, bulimia,obsessive-compulsive disease and obesity. Another preferred conditionmore specific to combinations including preferably duloxetine but alsovenlafaxine and milnacipran is urinary incontinence.

[0276] Depression in its many variations has recently become much morevisible to the general public than it has previously been. It is nowrecognized as an extremely damaging disorder, and one that afflicts asurprisingly large fraction of the population. Suicide is the mostextreme symptom of depression, but millions of people, not quite sodrastically afflicted, live in misery and partial or completeuselessness, and afflict their families as well by their affliction. Theintroduction of fluoxetine was a breakthrough in the treatment ofdepression, and depressives are now much more likely to be diagnosed andtreated than they were only a decade ago. Duloxetine is in clinicaltrials for the treatment of depression.

[0277] Depression is often associated with other diseases andconditions, or caused by such other conditions. For example, it isassociated with Parkinson's disease; with HIV; with Alzheimer's disease;and with abuse of anabolic steroids. Depression may also be associatedwith abuse of any substance, or may be associated with behavioralproblems resulting from or occurring in combination with head injuries,mental retardation or stroke. Depression in all its variations is apreferred target of treatment with the present adjunctive therapy methodand compositions.

[0278] Obsessive-compulsive disease appears in a great variety ofdegrees and symptoms, generally linked by the patient's uncontrollableurge to perform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted patient may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

[0279] Obesity is a frequent condition in the American population. Ithas been found that fluoxetine will enable an obese patient to loseweight, with the resulting benefit to the patient's circulation andheart condition, as well as general well being and energy.

[0280] Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles. Duloxetine controls both types of incontinence, or bothtypes at once, and so is important to the many people who suffer fromthis embarrassing and disabling disorder.

[0281] The present combination is useful for treating many otherdiseases, disorders and conditions as well, as set out below. In manycases, the diseases to be mentioned here are classified in theInternational Classification of Diseases, 9th Edition (ICD), or in theDiagnostic and Statistical Manual of Mental Disorders, 3rd VersionRevised, published by the American Psychiatric Association (DSM). Insuch cases, the ICD or DSM code numbers are supplied below for theconvenience of the reader.

[0282] depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82,293.83, 310.10, 318.00, 317.00

[0283] migraine

[0284] pain, particularly neuropathic pain

[0285] bulimia, ICD 307.51, DSM 307.51

[0286] premenstrual syndrome or late luteal phase syndrome, DSM 307.90

[0287] alcoholism, ICD 305.0, DSM 305.00 & 303.90

[0288] tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

[0289] panic disorder, ICD 300.01, DSM 300.01 & 300.21

[0290] anxiety, ICD 300.02, DSM 300.00

[0291] post-traumatic syndrome, DSM 309.89

[0292] memory loss, DSM 294.00

[0293] dementia of aging, ICD 290

[0294] social phobia, ICD 300.23, DSM 300.23

[0295] attention deficit hyperactivity disorder, ICD 314.0

[0296] disruptive behavior disorders, ICD 312

[0297] impulse control disorders, ICD 312, DSM 312.39 & 312.34

[0298] borderline personality disorder, ICD 301.83, DSM 301.83

[0299] chronic fatigue syndrome

[0300] premature ejaculation, DSM 302.75

[0301] erectile difficulty, DSM 302.72

[0302] anorexia nervosa, ICD 307.1, DSM 307.10

[0303] disorders of sleep, ICD 307.4

[0304] autism

[0305] mutism

[0306] trichotillomania

[0307] Further, the compounds of Formula I or formula Ia areparticularly useful for alleviating the symptoms of smoking cessation ornicotine withdrawal when administered in combination with a serotoninreuptake inhibitor. The SRI's to be used in this treatment method, andthe administration methods and formulations, are as described above. Theuse of the present compounds with SRI's in patients striving to stop useof tobacco or nicotine provides surprisingly complete alleviation of theusual painful and damaging symptoms of such patients, includingnervousness, irritability, craving, excessive appetite, anxiety,depression in many forms, inability to concentrate, and the like.

[0308] Therapeutic Applications

[0309] The compounds of Formula I or formula Ia are useful for otherimportant therapeutic purposes, as well as in combination with SRIs andin nicotine withdrawal or smoking cessation cases. In particular, thecompounds are useful for antagonism at the serotonin 1A receptor andaccordingly are used for the treatment or prevention of conditionscaused by or affected by excessive activity of that receptor.

[0310] More particularly, the compounds of Formula I or formula Ia areuseful in the treatment of anxiety, depression, hypertension, cognitivedisorders, psychosis, sleep disorders, gastric motility disorders,sexual dysfunction, brain trauma, memory loss, appetite disorders andobesity, substance abuse, obsessive-compulsive disease, panic disorderand migraine.

[0311] Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02. A furtherparticularly noted disorder is depression and the group ofdepression-related disorders, which are discussed above in thediscussion of adjunctive therapy with SRIs.

[0312] Pharmaceutical Compositions

[0313] It is customary to formulate pharmaceuticals for administration,to provide control of the dosage and stability of the product inshipment and storage, and the usual methods of formulation are entirelyapplicable to the compounds of Formula I and formula Ia. Suchcompositions, comprising at least one pharmaceutically acceptablecarrier, are valuable and novel because of the presence of the compoundsof Formula I or formula Ia therein. Although pharmaceutical chemists arewell aware of many effective ways to formulate pharmaceuticals, whichtechnology is applicable to the present compounds, some discussion ofthe subject will be given here for the convenience of the reader.

[0314] The usual methods of formulation used in pharmaceutical scienceand the usual types of compositions may be used, including tablets,chewable tablets, capsules, solutions, parenteral solutions, intranasalsprays or powders, troches, suppositories, transdermal patches andsuspensions. In general, compositions contain from about 0.5% to about50% of the compound in total, depending on the desired dose and the typeof composition to be used. The amount of the compound of Formula I orformula Ia, however, is best defined as the effective amount, that is,the amount of the compound which provides the desired dose to thepatient in need of such treatment. The activity of the compounds do notdepend on the nature of the composition, so the compositions are chosenand formulated solely for convenience and economy. Any compound may beformulated in any desired form of composition. Some discussion ofdifferent compositions will be provided, followed by some typicalformulations.

[0315] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

[0316] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0317] A lubricant is necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0318] Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

[0319] Enteric formulations are often used to protect an activeingredient from the strongly acidic contents of the stomach. Suchformulations are created by coating a solid dosage form with a film of apolymer which is insoluble in acidic environments, and soluble in basicenvironments. Exemplary films are cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate andhydroxypropyl methylcellulose acetate succinate.

[0320] Tablets are often coated with sugar as a flavor and sealant, orwith film-forming protecting agents to modify the dissolution propertiesof the tablet. The compounds may also be formulated as chewable tablets,by using large amounts of pleasant-tasting substances such as mannitolin the formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the patient consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some patients.

[0321] When it is desired to administer the combination as asuppository, the usual bases may be used. Cocoa butter is a traditionalsuppository base, which may be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use, also.

[0322] Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

[0323] The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1

[0324] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Example 1  20 mg Starch, dried 200 mgMagnesium stearate  10 mg Total 230 mg

Formulation 2

[0325] A tablet is prepared using the ingredients below: Quantity(mg/capsule) Example 2  10 mg Cellulose, microcrystalline 400 mg Silicondioxide, fumed  10 mg Stearic acid  5 mg Total 425 mg

[0326] The components are blended and compressed to form tablets eachweighing 425 mg.

Formulation 3

[0327] Tablets, each containing 10 mg of active ingredient, are made asfollows: Example 3  10 mg Starch  45 mg Microcrystalline cellulose  35mg Polyvinylpyrrolidone  4 mg (as 10% solution in water) Sodiumcarboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc  1 mg Total100 mg

[0328] The active ingredient, starch and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solutioncontaining polyvinyl-pyrrolidone is mixed with the resultant powder, andthe mixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C. and passed through a No. 18mesh U.S. Sieve. The sodium carboxymethyl starch, magnesium stearate andtalc, previously passed through a No. 60 mesh U.S. sieve, are then addedto the granules which, after mixing, are compressed on a tablet machineto yield tablets each weighing 100 mg.

Formulation 4

[0329] Capsules, each containing 30 mg of active ingredient, are made asfollows: Example 4  30 mg Starch  59 mg Microcrystalline cellulose  59mg Magnesium stearate  2 mg Total 150 mg

[0330] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 mesh U.S. sieve, and filled intohard gelatin capsules in 150 mg quantities.

Formulation 5

[0331] Suppositories, each containing 5 mg of active ingredient, aremade as follows: Example 5    5 mg Saturated fatty acid glycerides 2,000mg Total 2,005 mg

[0332] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 6

[0333] Suspensions, each containing 10 mg of active ingredient per 5 mldose, are made as follows: Example 6   10 mg Sodium carboxymethylcellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavorq.v. Color q.v. Purified water to total   5 ml

[0334] The active ingredient is passed through a No. 45 mesh U.S. sieveand mixed with the sodium carboxymethyl cellulose and syrup to form asmooth paste. The benzoic acid solution, flavor and color are dilutedwith a portion of the water and added, with stirring. Sufficient wateris then added to produce the required volume.

Formulation 7

[0335] An intravenous formulation may be prepared as follows: Example 7 10 mg Isotonic saline 1,000 ml

Formulation 8

[0336] Hard gelatin capsules are prepared in a manner analogous toformulation 1 using the following ingredients: Quantity (mg/capsule)(+)-1-(2-Methoxyphenyl)-4-[3-  20 mg (cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine HCl Starch, dried 200 mg Magnesium stearate  10mg Total 230 mg

Formulation 9

[0337] A tablet is prepared using the ingredients below: Quantity(mg/capsule) (+)-1-(2-Methoxyphenyl)-4-[3-  10 mg(cyclohexanecarbonyl)-3- (phenyl)butyl] piperazine HCl Cellulose,microcrystalline 400 mg Silicon dioxide, fumed  10 mg Stearic acid  5 mgTotal 425 mg

[0338] The components are blended and compressed to form tablets eachweighing 425 mg in a manner analogous to formulation 2.

Formulation 10

[0339] Tablets, each containing 10 mg of active ingredient, are made asfollows: (+)-1-(2-Methoxyphenyl)-4-[3-  10 mg (cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine HCl Starch  45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water)  4 mg Sodiumcarboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc  1 mg Total100 mg

[0340] The active ingredient, starch and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solutioncontaining polyvinyl-pyrrolidone is mixed with the resultant powder, andthe mixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C. and passed through a No. 18mesh U.S. Sieve. The sodium carboxymethyl starch, magnesium stearate andtalc, previously passed through a No. 60 mesh U.S. sieve, are then addedto the granules which, after mixing, are compressed on a tablet machineto yield tablets each weighing 100 mg.

Formulation 11

[0341] Capsules, each containing 30 mg of active ingredient, are made asfollows in a manner analogous to formulation 4:(+)-1-(2-Methoxyphenyl)-4-[3-  30 mg cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine HCl Starch  59 mg Microcrystalline cellulose 59 mg Magnesium stearate  2 mg Total 150 mg

What is claimed is:
 1. A process for the preparation of a compound ofthe formula II:

wherein R¹ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio;R² is phenyl, naphthyl or (C₃-C₁₂)cycloalkyl substituted with one or twosubstituents selected from the group consisting of hydrogen(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo; R³ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo, comprising, treating a compound of formula III

wherein R¹, R² and R³ are described as above, with a suitable base and acompound of formula IV:

wherein X is a suitable leaving group, to provide the compound offormula V

and oxidizing the compound of formula V with a suitable oxidizing agentto provide the compound of formula II.
 2. A process according to claim 1wherein R¹ is CH₃; R² is cyclohexyl; and R³ is hydrogen.
 3. A processaccording to claim 2 wherein X is Br or Cl.
 4. A process according toclaim 3 wherein the suitable oxidizing agent is ozone.
 5. A processaccording to claim 4 wherein the suitable base is potassiumtert-butoxide.
 6. A compound of the formula:

wherein R¹ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio;R² is phenyl, naphthyl or (C₃-C₁₂)cycloalkyl substituted with one or twosubstituents selected from the group consisting of hydrogen(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo; R³ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo.
 7. A compound according to claim 6 wherein R¹ is CH₃; R² iscyclohexyl; and R³ is hydrogen.